The synthesized 1,2,4-thiadiazole derivative displaying biological activity has low aqueous solubility and dissolution rate. Novel oral formulations of thiadiazole with βand hydroxypropyl-β-cyclodextrins were obtained by grinding and freeze-drying methods with the purpose to improve the aqueous solubility. Complex formation of 1,2,4-thiadiazole derivative with cyclodextrins was confirmed by means of solid-state 13 C MAS CP/TOSS NMR. Solubility, dissolution rate and permeability of the solid inclusion complexes were evaluated in different biorelevant media (SGF, FaSSGF, FaSSIF) simulating the conditions in the gastrointestinal tract. It was demonstrated that the content of biorelevant media affects the properties of the inclusion complexes. In particular, solubilizing effect of cyclodextrins became less pronounced when the micelles of taurocholic acid and lecithin are formed in the dissolution media. The inclusion of thiadiazole into cyclodextrin cavity is in competition with its partitioning into the micelles and this should be taken into account when the in vivo behavior is predicted. The results of in vitro and in vivo experiments were found to be in agreement and showed the highest solubility, dissolution rate and bioavailability of the freeze-dried complexes of thiadiazole with hydroxypropyl-β-cyclodextrin. These complexes can be proposed as more effective dosage forms for oral administration.
Because of the problem to evaluate biological activity in water-soluble substances in all phases of preclinical and clinical studies, the research work enabled to develop the original solvent for poorly soluble compounds based on substances for parenteral nutrition. The main aim is to examine the impact of the original solvent based on substances for parenteral nutrition on biological systems exemplified by the hemostatic system, characterized by sensitivity and variability of the effects in response to any impact, and its comparison with the solvents that are conventional in pharmacological research. Experimental work is performed according to the “guidance on preclinical research of new pharmacological substances” in vitro. The findings show that traditional solvents at low dosages affect all the researched indicators of the hemostasis system. The smallest effect in respect of the hemostatic system was characterized by ethanol, and the most apparent antiaggregational effect was registered with dioxane. 10% concentration of original blend of lipids made no effect on hemostasis system. Thus, according to their own findings and experience in application of lipid emulsions as substances of parenteral nutrition, they can be considered to be an adequate solvent in all phases of preclinical and clinical studies of new drugs.
Background: Preventing and control of bleeding is important in various areas of clinical medicine in the light of increasing number of patients with hemorrhagic manifestations, extensive use of anticoagulants, increasing number of invasive diagnostic, and treatment methods. However, the drugs traditionally used in medical practice to control bleeding are often inefficient and unable to lead to effective reduction in blood loss. One of the ways to find new methods of bleeding prophylaxis is to develop means of pharmacological correction of hemostasis system. The results of the previous research show potentially high activity of some new nitrogen-containing heterocyclic derivatives relating to hemostasis system in vitro and in vivo. Aims and Objectives: To examine system hemostatic activity of first synthesized benzylammonium salt 2-[3-methyl-1-npropyl-7-(1,1-dioxothietanil-3) xantinyl-8-thio]acetic acid (Compound I) under experimental conditions in vitro and in vivo. Materials and Methods: Experimental work in vitro is performed on the blood of healthy male donors, under conditions in vivo it is done on intraperitoneal injection of equimolar concentrations of the test substances. Thromboelastography (TEG) was carried out with apparatus TEG 5000. The analysis of the thromboelastograms enabled to define general tendency of coagulation, functional activity of platelets and fibrinogen, fibrinolysis activity, and physicomechanical properties of the formed clots. The influence of firstly synthesized xanthine derivative and ethamsylate on the functional activity of platelets in vitro and in vivo was studied using a laser platelet aggregation analyzer "Biola 230LA." The research evaluated the general nature of aggregation, value of maximum aggregation, maximum rate of aggregation, and average size of platelet aggregates. Experimental evaluation of the system specific hemostatic activity in vivo was carried out using the model of parenchymatous bleeding in immature male rats. Results: The interference came amid registration of bleeding stop time and extent of blood loss. Proagregate effect of Compound I is successfully realized into the system hemostatic activity under conditions of parenchymatous bleeding, exceeding the performance of the control group and the etamsylate group. Conclusion: The findings reveal potentially high systemic hemostatic activity of Compound I, convincing of the need to further study this compound and its analogues to create on their basis highly efficient, selective correctors of hemostasis system.
Aim. To study the processes of free-radical oxidation, antioxidant defense, energy metabolism, electrolyte metabolism, and cytokine system reflecting the state of the non-specific defense of the body in workers exposed to complex of toxic substances under the conditions of manufacturing, substantiating the importance of indicators of preclinical diagnosis of disease development risk.Methods. The study included 90 workers of JSC «Experimental Plant Neftekhim», 95 workers of JSC «Kaustic» and 101 workers of JSC «Ufa plant of elastomeric materials, products and structures». Materials for the study were blood, mixed saliva, gingival fluid and urine. The laboratory studies were performed to evaluate the free radical oxidation processes, antioxidant defense, energy metabolism, electrolyte metabolism, and cytokine system. Taking into account the features of industrial factors, particularly their effects on the workers bodies, routes of toxic compounds entry by inhalation, oral cavity and skin of the hands, three professional groups were formed (A, B, C). Group A included employees having constant contact with chlororganic compounds. The group B included persons who have constant contact with the higher and lower aromatic hydrocarbons. A group C consisted of employees who have constant contact with a mixture of chemicals: rubber compound containing carcinogens - benzo(a)pyrene, NDMA, nitrosodiethylamine; white carbon black, rubber dust, talc, amine compounds, sulfur dioxide, carbon monoxide. The control group consisted of employees of administrative and managerial staff.Results. The study revealed that one of the major pathogenetic mechanisms of action of chemical and petrochemical industry hazards is activation of free radical oxidation.Conclusion. Among the mechanisms of the influence of chemical contaminants of working environment a leading role play intensification of free radical oxidation processes, failure and/or inhibition of the antioxidant defense components.
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